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Sodium Hydride / DMF process stopped

Scenario

A manufacturer had contracted out the R&D for a new product. The contractor
had spent some time optimizing the process and the isolation of the product, scaling
up as they went, up to a 10 litre scale. Before
the manufacturer would fund his three cGMP validation batches, it was decided to
have one large batch made by a sub-contractor (under non cGMP) to prove that the chemistry worked
and the isolation of the product was successful.

During the discussions with the chosen sub-contractor, the sub-contractor's Safety Scientist on
seeing the process, raised the point that the process used sodium hydride in
dimethylformamide and that the mixture was warmed. He then pointed out that
they could not possibly run this process in the pilot plant. This was a surprise
for the contractor (and the manufacturer) as they had seen many processes in the
literature using this mixture.

The Safety Scientist insisted it was unsafe to run and left to look up some firm
data to show the contractor. He showed them the papers published in
19821, & 2, the data in Bretherick3 plus unpublished data he had determined at another employment4.
The contractor left and the project was now almost certainly doomed to be terminated.

Lessons Learnt

There is no substitute for a fully trained Process Safety Specialist who has a good breadth of
knowledge to ensure that all processes being examined as potential plant candidates
will be safe as possible to implement

The main contractor should have picked this data up at an early stage. This would
have minimized the expenditure, and possibly would have allowed them time to seek
alternative routes to the product.

Conclusions

It is plain that the use of dimethylformamide (DMF) and sodium hydride continues on, mainly due to
chemists following old publication procedures.

The use of sodium hydride and dimethylformamide often proceeds without event,
especially on a small scale. It is only when the reaction is scaled up does
one encounter potential problems with runaway reactions

The runaway reaction observed between sodium hydride and dimethylformamide is
not very reproducible at plant scale. Some batches have successfully been made without incident.
This may well be due to the quality of the sodium hydride (traces of free sodium)
and the dimethylformamide (water content has been suggested).

Nevertheless, at least two pilot plant vessels at different locations have been
damaged by this mixture, so one must not look favourably on implementing a plant process
based on mixtures of sodium hydride and these protic solvents.

De Wall, G. Chem. Eng. News, 1982, 60(37), 5
A similar incident to (1), runaway started at 40°C, and rose 100° in less
than 10 minutes, boiling off most of the DMF. This was the fourth run of this process,
the other three passed without incident.

Bretherick

Unpublished Data, RPR, 1980s
Following the publication of (1) and (2), ARC runs on mixtures of sodium hydride with

Dimethylformamide (DMF)

Dimethylacetamide (DMA)

Dimethylimidazolindinone (DMI)

Dimethyl sulphoxide (DMSO)

were carried out. In all cases exothermic activity was recorded below 20°C